@article{243675d1e28f49b99d99ff1341ff8751,
title = "Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype",
abstract = "Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.",
keywords = "CAFs, HSP90, Nrf2, p53, small EVs",
author = "Shaolin Ma and McGuire, {Michael H.} and Mangala, {Lingegowda S.} and Sanghoon Lee and Elaine Stur and Wen Hu and Emine Bayraktar and Alejandro Villar-Prados and Cristina Ivan and Wu, {Sherry Y.} and Akira Yokoi and Dasari, {Santosh K.} and Jennings, {Nicholas B.} and Jinsong Liu and Gabriel Lopez-Berestein and Prahlad Ram and Sood, {Anil K.}",
note = "Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund{\textquoteright}s exRNA Communication Program. This work was supported in part by NIH grants R35CA209904 , UH3TR000943 , P50CA217685 , P50CA098258 , CA177909 , U01CA213759 , CA227622 , and P30CA016672 ; the Ovarian Cancer Research Alliance ; the Blanton-Davis Ovarian Cancer Research Program ; the American Cancer Society Research Professor Award; the Frank McGraw Memorial Chair in Cancer Research ; and the MD Anderson Ovarian Cancer Moon Shot Program . S.M. was supported by the Foundation for Women's Cancer research grant (sponsor award number FP00009883 ). S.Y.W. was supported by the Cancer Prevention & Research Institute of Texas Research Training Program (grants RP101502 , RP140106 , and RP170067 ). E.S. was supported by Ovarian Cancer Research Alliance (OCRA number FP00006137 ). We acknowledge Scientific Publications, Research Medical Library at The University of Texas MD Anderson Cancer Center for reviewing and editing this manuscript. We acknowledge High Resolution Electron Microscopy Facility ( NIH grant P30CA016672 ) at The University of Texas MD Anderson Cancer Center for performing the TEM studies. We acknowledge The Flow Cytometry and Cellular Imaging Core Facility (FCCICF) ( NCI grant P30CA16672 ) at The University of Texas MD Anderson Cancer Center for performing the cell sorting. Funding Information: This publication is part of the NIH Extracellular RNA Communication Consortium paper package and was supported by the NIH Common Fund's exRNA Communication Program. This work was supported in part by NIH grants R35CA209904, UH3TR000943, P50CA217685, P50CA098258, CA177909, U01CA213759, CA227622, and P30CA016672; the Ovarian Cancer Research Alliance; the Blanton-Davis Ovarian Cancer Research Program; the American Cancer Society Research Professor Award; the Frank McGraw Memorial Chair in Cancer Research; and the MD Anderson Ovarian Cancer Moon Shot Program. S.M. was supported by the Foundation for Women's Cancer research grant (sponsor award number FP00009883). S.Y.W. was supported by the Cancer Prevention & Research Institute of Texas Research Training Program (grants RP101502, RP140106, and RP170067). E.S. was supported by Ovarian Cancer Research Alliance (OCRA number FP00006137). We acknowledge Scientific Publications, Research Medical Library at The University of Texas MD Anderson Cancer Center for reviewing and editing this manuscript. We acknowledge High Resolution Electron Microscopy Facility (NIH grant P30CA016672) at The University of Texas MD Anderson Cancer Center for performing the TEM studies. We acknowledge The Flow Cytometry and Cellular Imaging Core Facility (FCCICF) (NCI grant P30CA16672) at The University of Texas MD Anderson Cancer Center for performing the cell sorting. Conceptualization: M.H.M. A.K.S. G.L.B. and S.M.; methodology, S.M. M.H.M. A.Y. and A.V.P.; investigation, S.M. M.H.M. W.H. L.S.M. E.B. E.S. A.V.P. S.D. S.Y.W. and N.B.J.; data curation, S.M. M.H.M. S.L. C.I. J.L. and P.R.; writing ? original draft, M.H.M. and S.M.; writing ? review & editing, all authors; resources: S.L. and J.L.; supervision, A.K.S. G.L.B. J.L. and P.R.; funding acquisition, A.K.S. and S.M. A.K.S. a consultant for Kiyatec, Astra Zeneca, and Merck, has received research funding from M-Trap, and is a Bio-Path Holdings stockholder. The remaining authors declare no competing interests. Funding Information: A.K.S. a consultant for Kiyatec, Astra Zeneca, and Merck, has received research funding from M-Trap, and is a Bio-Path Holdings stockholder. The remaining authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = feb,
day = "9",
doi = "10.1016/j.celrep.2021.108726",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}